Consistency Analysis of Genome-Scale Models of Bacterial Metabolism: A Metamodel Approach.

Genome-scale metabolic models usually contain inconsistencies that manifest as blocked reactions and gap metabolites. With the purpose to detect recurrent inconsistencies in metabolic models, a large-scale analysis was performed using a previously published dataset of 130 genome-scale models. The results showed that a large number of reactions (~22%) are blocked in all the models where they are present. To unravel the nature of such inconsistencies a metamodel was construed by joining the 130 models in a single network. This metamodel was manually curated using the unconnected modules approach, and then, it was used as a reference network to perform a gap-filling on each individual genome-scale model. Finally, a set of 36 models that had not been considered during the construction of the metamodel was used, as a proof of concept, to extend the metamodel with new biochemical information, and to assess its impact on gap-filling results. The analysis performed on the metamodel allowed to conclude: 1) the recurrent inconsistencies found in the models were already present in the metabolic database used during the reconstructions process; 2) the presence of inconsistencies in a metabolic database can be propagated to the reconstructed models; 3) there are reactions not manifested as blocked which are active as a consequence of some classes of artifacts, and; 4) the results of an automatic gap-filling are highly dependent on the consistency and completeness of the metamodel or metabolic database used as the reference network. In conclusion the consistency analysis should be applied to metabolic databases in order to detect and fill gaps as well as to detect and remove artifacts and redundant information.